Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

Area of Science:

• Microbiology
• Metabolic Research
• Drug Discovery

Background:

• Understanding gut microbiota-host interactions is crucial for metabolic health.
• Microbial enzymes can significantly influence host physiology.
• Dipeptidyl peptidase 4 (DPP4) plays a role in glucose regulation.

Purpose of the Study:

• To investigate the role of gut microbiota-derived enzymes in host physiology.
• To identify microbial DPP4 as an enzyme influencing glucose metabolism.
• To discover selective inhibitors of microbial DPP4.

Main Methods:

• Development of an enzyme activity-screening platform for microbial enzymes.
• Identification of bacterial taxa expressing DPP4.
• High-throughput screening for microbial DPP4 inhibitors.

Main Results:

• Specific bacterial taxa express microbial dipeptidyl peptidase 4 (DPP4).
• Microbial DPP4 reduces active glucagon-like peptide-1 (GLP-1) and impairs glucose metabolism in mice.
• Existing human DPP4 inhibitors (e.g., sitagliptin) are ineffective against microbial DPP4.
• Daurisolone-d4 (Dau-d4) was identified as a selective microbial DPP4 inhibitor.
• Dau-d4 improved glucose tolerance in diabetic mice.

Conclusions:

• Microbial DPP4 is a novel factor contributing to glucose metabolic disruption.
• Targeting microbial DPP4 offers a potential therapeutic strategy for metabolic diseases.
• Dau-d4 demonstrates promise as a selective inhibitor for treating metabolic disorders.